Citations

Mycobacterium septicum is a rarely identified nontuberculous mycobacterium capable of causing infections in both healthy and immunocompromised individuals. Only a few cases of M. septicum infections have been reported, which makes recognizing corresponding clinical disease more challenging for clinicians. Antimicrobial susceptibility profiles for this organism are not well described, and corresponding optimal therapeutic regimens have not been established. We report a tertiary care center’s experience with M. septicum from 2014 to 2020.

Abstract Background: Disease relapse is observed in a significant proportion of HER2-positive breast cancer (BC) patients with residual disease (RD) after neoadjuvant treatment, as well as in a subgroup of those achieving pathological complete response (pCR). As the host immune response plays a key role in modulating the activity of anti-HER2 agents, we investigated the association of T- and B-cell receptor (TCR and BCR) repertoires with pCR and event-free survival (EFS) in the NeoALTTO phase 3 trial. Methods: RNA sequencing (RNAseq) data from baseline tumor biopsies were available for 254 patients out of the 455 enrolled in the study. Among those, 166 did not achieve a pCR defined as ypT0/is. Matched RNAseq data from RD samples were available for 43 cases. TCR/BCR repertoires were extracted from RNAseq data using the MiXCR software. TCR and BCR read counts, number of clones, evenness, Shannon entropy, Gini index, length of the complementarity determining region 3, top and second top clone proportion were evaluated. Survival analysis was performed using univariate and multivariate (adjusted for tumor size, nodal status, grade, estrogen receptor [ER] status, age and treatment arm) Cox proportional hazard models, while logistic regressions were used for pCR. False discovery rate (FDR) was obtained using Benjamini & Hochberg method. Results: Baseline TCR top (odds ratio [OR]=0.63 [95% CI 0.46-0.87], FDR=0.021) and second top (OR=0.57 [0.41-0.79], FDR=0.004) clone proportion were significantly associated with a lower probability of achieving pCR in the multivariate analysis. BCR evenness (hazard ratio [HR]=1.5 [1.2-2], FDR=0.015) and Gini index (HR=0.66 [0.52-0.85], FDR=0.015) were significantly associated with EFS in the multivariate analysis. In residual disease, BCR evenness and Gini index showed a similar trend in the EFS univariate analysis, while TCR read counts, number of clones, and entropy were associated with lower HR (P<0.05), although FDR were borderline significant (0.05<FDR<0.1). A model to predict EFS including baseline BCR evenness, ER status, stromal tumor-infiltrating lymphocyte level, and pCR was able to identify 3 groups with good, intermediate and poor prognosis (Kaplan-Meier 5-year EFS rates of 95%, 80% and 58%, respectively). Of note, about 63%, 45% and 12% of the patients achieved a pCR in the three prognostic groups, respectively. Conclusions: In the NeoALTTO trial, the presence of an evenly distributed BCR repertoire was associated with worse EFS. A model integrating baseline immune-related and clinical features was able to identify patients with excellent prognosis despite RD or, conversely, with poor prognosis after pCR. We envision that our model has the potential to allow the personalization of post-operative treatment strategies after both pCR and RD in HER2-positive BC. Further validation of our findings is warranted. Citation Format: Mattia Rediti, David Venet, Françoise Rothé, Tao Qing, Marion Maetens, Ian Bradbury, Miguel A. Izquierdo, Serena Di Cosimo, Florentine Hilbers, Mohammed Bajji, Nadia Harbeck, Michael Untch, David L. Rimm, Stephen Chia, Minetta C. Liu, Cristina Saura, Jens Huober, Paolo Nuciforo, Roberto Salgado, Sherene Loi, Lajos Pusztai, Christos Sotiriou. Predictive and prognostic role of T- and B-cell receptor repertoire in HER2-positive breast cancer: An analysis of the NeoALTTO clinical trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1998.

In vivo MRS is a non‐invasive measurement technique used not only in humans, but also in animal models using high‐field magnets. MRS enables the measurement of metabolite concentrations as well as metabolic rates and their modifications in healthy animals and disease models. Such data open the way to a deeper understanding of the underlying biochemistry, related disturbances and mechanisms taking place during or prior to symptoms and tissue changes. In this work, we focus on the main preclinical 1H, 31P and 13C MRS approaches to study brain metabolism in rodent models, with the aim of providing general experts’ consensus recommendations (animal models, anesthesia, data acquisition protocols). An overview of the main practical differences in preclinical compared with clinical MRS studies is presented, as well as the additional biochemical information that can be obtained in animal models in terms of metabolite concentrations and metabolic flux measurements. The properties of high‐field preclinical MRS and the technical limitations are also described.

8521 Background: Several clinical and molecular prognostic factors (e.g, International Staging System [ISS] stage, plasma cell labeling index, genomic models) exist for multiple myeloma (MM). We hypothesized that exploiting gene signatures representative of oncogenic pathway deregulation (i.e., Ras, Myc, etc.), would improve MM prognostication and also aid with the identification of novel therapeutic targets. Methods: Using a discovery cohort (n=47) of patients with MM and corresponding gene expression data, we built upon current molecular risk-stratification and devised a Bayesian genomic (“metagene”) model for prognosis. We validated that model in an independent patient cohort (n=207). Finally, we incorporated ISS staging and clinical variables to construct a combined Clinico-Genomic Risk Stratification System. We further validated the combined model in a separate cohort (n=72), in a blinded manner. Results: Using gene signatures predictive of oncogenic pathway activation in the discovery cohort, we identified specific patterns (metagenes) of signaling pathway activation with prognostic relevance. In an independent validation cohort, this metagene-based model accurately predicted event free survival (EFS) independently of ISS (multivariate hazard ratio [HR] 3.4 for ISS stage, and 5.4 for the metagene model, p=0.002). Using multivariate risk modeling, we incorporated ISS staging and the metagene model into a Clinico-Genomic System and successfully stratified the validation cohort into three groups (low, intermediate, and high risk) with markedly different EFS (HR 4.2 for intermediate risk and 14.0 for high risk vs. the low risk cohort, p<0.0001). In an additional blinded validation, the Clinico-Genomic System again accurately predicted median overall survival (68.7 [low risk] vs 24.7 [intermediate risk] vs 18.7 months [high risk], p<0.0001); more accurately than either ISS or other reported genomic models. Conclusions: A combined Clinico-Genomic Risk Stratification System, building on patterns of oncogenic pathway activation and ISS staging system, improves upon current prognostic models in MM and identifies novel pathway targets for future therapeutic consideration. No significant financial relationships to disclose.

Abstract Aims Coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been associated with cardiovascular features of myocardial involvement including elevated serum troponin levels and acute heart failure with reduced ejection fraction. The cardiac pathological changes in these patients with COVID-19 have yet to be well described. Methods and results In an international multicentre study, cardiac tissue from the autopsies of 21 consecutive COVID-19 patients was assessed by cardiovascular pathologists. The presence of myocarditis, as defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analysed by immunohistochemistry. Other forms of acute myocyte injury and inflammation were also described, as well as coronary artery, endocardium, and pericardium involvement. Lymphocytic myocarditis was present in 3 (14%) of the cases. In two of these cases, the T lymphocytes were CD4 predominant and in one case the T lymphocytes were CD8 predominant. Increased interstitial macrophage infiltration was present in 18 (86%) of the cases. A mild pericarditis was present in four cases. Acute myocyte injury in the right ventricle, most probably due to strain/overload, was present in four cases. There was a non-significant trend toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. Disrupted coronary artery plaques, coronary artery aneurysms, and large pulmonary emboli were not identified. Conclusions In SARS-CoV-2 there are increased interstitial macrophages in a majority of the cases and multifocal lymphocytic myocarditis in a small fraction of the cases. Other forms of myocardial injury are also present in these patients. The macrophage infiltration may reflect underlying diseases rather than COVID-19.

Clinical trials are a key component of the evidence base for the treatment of headache disorders. In 1991, the International Headache Society Clinical Trials Standing Committee developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Migraine. Advances in drugs, devices, and biologicals, as well as novel trial designs, have prompted several updates over the nearly 30 years since, including most recently the Guidelines for controlled trials of preventive treatment of chronic migraine (2018), the Guidelines for controlled trials of acute treatment of migraine attacks in adults (2019), and Guidelines for controlled trials of preventive treatment of migraine in children and adolescents (2019). The present update incorporates findings from new research and is intended to optimize the design of controlled trials of preventive pharmacological treatment of episodic migraine in adults. A guideline for clinical trials with devices will be published separately.

BackgroundStudies have reported racial disparities in access to and use of multiple myeloma (MM) treatments between African American (AA) and White patients. Although AA patients demonstrate longer disease‐specific survival, this has not uniformly translated into improved survival over time. The association between race and treatment patterns and survival outcomes was analyzed using data from the Connect MM Registry.MethodsThe Connect MM Registry is a large US, multicenter, prospective observational cohort study of patients with newly diagnosed MM. Patients who received first‐line (1L) stem cell transplantation (SCT) or who did not receive SCT (non‐SCT or non–stem cell transplantation [NSCT]) were grouped by raceEffects of race and transplantation status on the use of triplet treatment were estimated using logistic regression.ResultsTreatment patterns in 1L (types and duration of induction, posttransplantation maintenance) were similar between AA and White patients. SCT rates in 1L (32% vs 36%) and triplet treatment use (AA: 44% for NSCT patients and 72% for SCT patients; and White: 48% for NSCT patients and 72% for SCT patients) during first induction were similar. No significant effect of race or transplantation status on 1L triplet treatment use was observed. Race was not found to be associated with survival outcomes among patients who underwent NSCT; however, AA patients who received SCT had significantly longer overall survival compared with White patients who underwent SCT (not reached vs 88.2 months; hazard ratio, 0.56; 95% CI, 0.35‐0.89 [P = .0141]).ConclusionsAA and White patients were found to have similar treatment patterns in the Connect MM Registry, suggesting that both groups had equal access to health care. In this real‐world setting, AA patients received standard‐of‐care treatment, which might have contributed to better MM‐specific survival compared with White patients.